Boronic acid containing molecules, such as arylboronic acids, are employed in a broad range of biological, medicinal and synthetic applications, including pharmaceutical compositions.
They are employed in applications such as carbohydrate recognition (for recent reviews see, e.g., Wulff, Pure Appl. Chem. 1982, 2093-2102; James et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 1910-1922). Also, arylboronic acids can be crucial synthetic intermediates or potential inhibitors of therapeutically relevant serine protease enzymes (for recent examples see, e.g., Kettner et al., J. Biol. Chem. 1984, 259, 15106; Martichonok et al., J. Am. Chem. Soc. 1996, 118, 950-958; Tian et al.; J. Org. Chem. 1997, 62, 514-522; Zhong et al., J. Am. Chem. Soc. 1995, 117, 7048; Priestley et al., Org. Lett. 2000, 2, 3095-3097). Boronic acids have also been applied in neutron capture therapy for cancer (for reviews see, e.g., Barth et al., Sci. Am. 1990, 263, 68-73; Hawthorne, Angew. Chem. Int. Ed. Engl. 1993, 32, 950-984; Mehta et al., Pharm. Res. 1996, 13, 344-351; Soloway et al., Chem. Rev. 1998, 1515-1562), and as transmembrane transport agents (for a recent review, see, e.g., Smith et al., Adv. Supramol. Chem. 1999, 5, 157-202 and references cited therein).
In recent years, boronic acids have also gained tremendous popularity as substrates and building blocks in organic synthesis and combinatorial chemistry. They have found widespread use in Suzuki cross-coupling reactions (see, e.g., Suzuki, Organometal. Chem. 1999, 576, 147-168; Suzuki, A., in “Metal-catalyzed Cross-coupling Reactions”, Eds. Diederich, F., et al., Wiley-VCH, 1997, Chapt. 2). Suzuki cross-coupling reactions (see, e.g., Suzuki (1999) Organometal. Chem. 576:147-168; Suzuki, A., in Metal-catalyzed cross-coupling reactions, Eds. Diederich, F., et al., Wiley-VCH, 1997, Chapt. 2) are commonly used in industrial and pharmaceutical chemistries. They can also provide novel biphenyl units, such as those represented in several biologically active molecules (see, e.g., Duncia (1992) Medical Research Reviews 12:149). Many new types of synthetic transformations that use boronic acids have created a demand for the commercial availability of a larger number of functionalized boronic acids.
However, in spite of the demand for boronic acids, particularly arylboronic acids, and conjugated forms of these compounds, there remains a shortage of commercially available supplies. The paucity of boronic acids can be explained by the non-existence of natural ones, and in large part by difficulties associated with the synthesis and derivatization of even the simplest functionalized ones by solution-phase methods.
The isolation of compounds containing a boronic acid functionality can prove notoriously troublesome due to their amphiphilic character. These problems are amplified when the desired boronic acid-containing compound comprises other sites with basic or acidic functionalities. Boronic acids are also typically slow moving on silica gel, and consequently must often be purified by recrystallization. In addition, boronic acids can be sensitive to oxidation (see, e.g., Snyder et al., J. Am. Chem. Soc. 1938, 60, 105-111; Matteson, J. Am. Chem. Soc. 1960, 82, 4228-4233). Some of these problems can be alleviated by protection of the boronic group as an ester (see, e.g., Matteson, D. S. Stereodirected Synthesis with Organoboranes, Springer:1995, Berlin, Heidelberg, p. 17 (section 1.4.2). However, these approaches require additional synthetic operations.
Solid-phase methods circumvent the need for aqueous work-up and other time-consuming operations required to isolate the desired boronic acid from excess reagents and by-products. Solid-phase Suzuki reactions in “one resin-bound substrate” schemes have been described, e.g., by Frenette (1994) Tetrahedron Lett. 35:9177-9180; Huwe (1999) Tetrahedron Lett. 40:683-686; Chamoin (1998) Tetrahedron Lett. 39:4179-4182. Two resin systems, also called resin-to-resin transfer reactions (RRTR), constitutes a significant simplification of solid-phase organic synthesis (SPOS). RRTR can be extremely valuable as a time saving strategy in combinatorial chemistry (see, e.g., Hamuro (1999) J. Am. Chem. Soc. 121:1636-1644). In RRTR, one resin-bound substrate is transferred to solution-phase by action of a phase-transfer agent or chaperone, and coupled in situ to another resin-bound substrate.
In view of all the above mentioned impediments in handling boronic acid containing molecules by solution-phase methods, it is clear that simple and general solid-phase approaches for their use, immobilization and derivatization would be of tremendous usefulness.